Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal prion disorder of humans that escapes detection until autopsy. The principal cause of neurotoxicity in this and other prion disorders is accumulation of PrP-scrapie (PrPSc), a ?-sheet rich isoform of prion protein (PrPC) in the brain parenchyma. Participation of other processes is suspected, but their mechanism of action is unclear. Emerging evidence indicates that imbalance of iron homeostasis is a consistent feature of affected brains, implicating redox-iron in disease associated neurotoxicity. Unlike Alzheimer's disease (AD) where diseased brains accumulate iron, brains from sCJD and scrapie infected animal models reveal a phenotype of 'functional'iron deficiency as suggested by a significant increase in the iron uptake protein transferrin (Tf) despite minimal change in brain iron levels. Moreover, Tf levels increase with disease progression in direct correlation with PrPSc, suggesting a cause and effect relationship with disease pathogenesis. Surprisingly, instead of a compensatory increase, levels of Tf are significantly decreased in the cerebrospinal-fluid (CSF) of sCJD cases much before end-stage disease, indicating mis-regulation of signaling between iron starved brain parenchymal cells and the blood-brain and brain-CSF barriers involved in iron transport from the peripheral circulation to the brain and secretion of brain Tf respectively. Based on these observations, we hypothesize that sCJD associated disruption of brain iron regulation causes specific changes in CSF levels of iron management proteins that correlate with disease progression, providing disease specific biomarker(s) for sCJD.
Two specific aims are proposed to test this hypothesis.
In aim 1, the mechanism underlying decreased CSF Tf in sCJD brains will be explored using scrapie infected mice as models. Specifically, change in brain iron levels during scrapie infection, correlation between brain iron and PrPSc levels, and change in iron transport from the peripheral circulation to the brain will be monitored by tracking transport of radiolabeled iron (59Fe) from the tail vein to the brain and CSF compartments during prion disease progression. 59Fe counts in the brain and CSF will be correlated with levels of iron management proteins to evaluate the integrity of brain iron signaling mechanisms.
In aim 2, the specificity and sensitivity of CSF Tf and other iron management proteins, the 'new'biomarkers, will be compared with 'current'surrogate CSF biomarkers of sCJD. The accuracy of new biomarkers in differentiating sCJD from rapidly progressive dementia and AD, potentially treatable causes of dementias often misdiagnosed as sCJD, will be emphasized. The prognostic reliability of new biomarkers will be assessed in CSF samples collected at different time points during disease progression from scrapie infected mice and Chronic Wasting Disease infected cervids, and the earliest time-point of a significant change will be identified. Successful completion of these studies will improve our understanding of the mechanism leading to decreased CSF Tf in sCJD, and facilitate the development of a rapid, specific, and sensitive pre-mortem diagnostic test for sCJD.

Public Health Relevance

Prion disorders are a group of invariably fatal neurodegenerative conditions of humans and animals that are sporadic and infectious in nature. Currently, the only reliable diagnostic test for these disorders is post- mortem, posing a risk of disease transmission from undiagnosed cases to healthy individuals. Our data indicate that the iron transport protein transferrin is decreased in the cerebrospinal fluid (CSF) of sporadic Creutzfeldt-Jakob disease (sCJD) cases. In this application we will investigate the underlying mechanism of this change, and whether CSF Tf and other iron management proteins can be used as a diagnostic biomarker for sCJD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Wong, May
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Case Western Reserve University
Schools of Medicine
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Tripathi, Ajai K; Singh, Neena (2016) Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease. J Alzheimers Dis 51:107-21
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Haldar, Swati; Beveridge, 'alim J; Wong, Joseph et al. (2013) A low-molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD. Antioxid Redox Signal 19:1662-75
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Singh, Ajay; Beveridge, Alim J; Singh, Neena (2011) Decreased CSF transferrin in sCJD: a potential pre-mortem diagnostic test for prion disorders. PLoS One 6:e16804